Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of major depression. However, there is also evidence that SSRIs may be significantly less effective than tricyclic antidepressants (TCAs) for depressed patients with melancholia. This issue is of particular concern in late-life major depression. SSRIs have important safety advantages with respect to overdose and a benign cardiovascular profile. Furthermore, the SSRIs do not have significant anticholinergic effects, and appear to be better tolerated than the TCAs. Perhaps most important, the SSRIs are currently widely prescribed as the medication treatment of first choice for major depression in late-life. Therefore, if it were determined that SSRIs are considerably less effective than TCAs in the treatment of melancholia in the elderly, there would be significant ramifications for clinical practice. Using a randomized, double-blind, parallel group design, the applicants will compare the efficacy and safety of a SSRI (sertraline) and a TCA (nortriptyline) in outpatients over the age of 60 who meet DSM-IV criteria for unipolar major depression, excluding patients who meet criteria for psychotic or atypical subtype. The randomization will be stratified by the presence or absence of melancholia. Outcome measures for the 12-week acute phase will include clinician and patient ratings of symptoms, side effects, and an evaluation of the health-related quality of life (HRQOL). At the end of the acute treatment phase, patients who meet criteria for clinical response will participate in a 6-month continuation phase. The applicants will test the hypothesis that the medication condition interacts with diagnostic subtype (melancholic vs. non-melancholic) in determining antidepressant response. The applicants predict that among melancholic patients nortriptyline will be superior to sertraline in efficacy, whereas among non-melancholic patients, nortirptyline and sertraline will have equal efficacy. The roles of symptom severity and alternative diagnostic subtyping in contributing to this pattern will be examined. The applicants predict that speed of response will be faster with the TCA, independent of subtype. Failure to show substantial improvement early in treatment may have greater predictive value for final TCA than for final SSRI nonresponse, indicating a need for longer SSRI treatment in the elderly. Finally, The applicants expect HRQOL to show continued improvement during the continuation phase in euthymic patients and an advantage for the SSRI in HRQOL improvement due to a superior side effect profile.